Derivatives of sulphonamides, their preparation and use as medicaments

ABSTRACT

The present invention relates to new derivatives of sulphonamides, with the general formula (I), as well as to their physiologically acceptable salts, the processes for their preparation, their application as medicaments in human and/or veterinary therapy and the pharmaceutical compositions that contain them.

FIELD OF THE INVENTION

The present invention relates to new derivatives of sulphonamides, withthe general formula (I), as well as to their physiologically acceptablesalts, the processes for their preparation, their application asmedicaments in human and/or veterinary therapy and the pharmaceuticalcompositions that contain them.

The new compounds object of the present invention can be used in thepharmaceutical industry as intermediates and for preparing medicaments.

BACKGROUND OF THE INVENTION

The superfamily of serotonin receptors (5-HT) includes 7 classes(5-HT₁-5-HT₇) encompassing 14 human subclasses [D. Hoyer, et al.,Neuropharmacology, 1997, 36, 419]. The 5-HT₆ receptor is the latestserotonin receptor identified by molecular cloning both in rats [F. J.Monsma, et al., Mol. Pharmacol., 1993, 43, 320; M. Ruat, et al.,Biochem. Biophys. Res. Commun., 1993, 193, 268] and in humans [R. Kohen,et al., J. Neurochem., 1996, 66, 47]. Compounds with 5-HT₆ receptorantagonistic activity are useful for the treatment of various disordersof the Central Nervous System and of the gastrointestinal tract, such asirritable intestine syndrome. Compounds with 5-HT₆ receptor antagonisticactivity are useful in the treatment of anxiety, depression andcognitive memory disorders [M. Yoshioka, et al., Ann. NY Acad. Sci.,1998, 861, 244; A. Bourson, et al., Br. J. Pharmacol., 1998, 125, 1562;D. C. Rogers, et al., Br. J. Pharmacol. Suppl., 1999, 127, 22P; A.Bourson, et al., J. Pharmacol. Exp. Ther., 1995, 274, 173; A. J.Sleight, et al., Behav. Brain Res., 1996, 73, 245; T. A. Branchek, etal., Annu. Rev. Pharmacol. Toxicol., 2000, 40, 319; C. Routledge, etal., Br. J. Pharmacol., 2000, 130, 1606]. It has been shown that typicaland atypical antipsychotic drugs for treating schizophrenia have a highaffinity for 5-HT₆ receptors (B. L. Roth, et al., J. Pharmacol. Exp.Ther., 1994, 268, 1403; C. E. Glatt, et al., Mol. Med., 1995, 1, 398; F.J. Mosma, et al., Mol. Pharmacol., 1993, 43, 320; T. Shinkai, et al.,Am. J. Med. Genet., 1999, 88, 120]. Compounds with 5-HT₆ receptorantagonistic activity are useful for treating infant hyperkinesia (ADHD,attention deficit/hyperactivity disorder) [W. D. Hirst, et al., Br. J.Pharmacol., 2000, 130, 1597; C. Gérard, et al., Brain Research, 1997,746, 207; M. R. Pranzatelli, Drugs of Today, 1997, 33, 379]. Patentapplication WO 01/32646 describes sulphonamides derived of bicycles,with 6 members each, aromatic or heteroaromatic with 5-HT₆ receptorantagonistic activity. Patent application EP 0733628 describessulphonamides derived of indole with an 5-HT_(1F) receptor antagonisticactivity useful for treating migraines. In general, the study of thescientific literature and patents indicates that small structuralvariations give rise to agonist or antagonist compounds of variousreceptors of serotonin that are useful for treating different diseases,depending on the receptor for which they show affinity.

After laborious research the inventors have managed to synthesize newcompounds with the general formula (I) that show interesting biologicalproperties making them particularly useful for use in human and/orveterinary therapy.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides new compounds with 5-HT₆ serotoninreceptor antagonistic activity useful in the preparation of a medicamentfor prevention or treatment of various disorders of the Central NervousSystem, and in particular anxiety, depression, cognitive memorydisorders and senile dementia or other dementia processes in which thereis a predominant cognition deficit, psychosis, infant hyperkinesia(ADHD, attention deficit/hyperactivity disorder) and other disordersmediated by the 5-HT₆ serotonin receptor in mammals, including man.

The compounds object of the present invention have the general formula(I)

wherein

-   A represents a substituent selected from among:    -   A heteroaromatic ring of 5 or 6 members containing 1 or 2        heteroatoms selected from among oxygen, nitrogen and sulphur,        optionally substituted by 1 or 2 halogen atoms, by a C₁-C₄ alkyl        radical or by a phenyl or heteroaryl radical with 5 or 6 members        containing 1 or 2 atoms of oxygen, nitrogen or sulphur:    -   A bicyclic heteroaromatic ring containing 1 to 3 heteroatoms        selected from among oxygen, nitrogen and sulphur, optionally        substituted by 1 or 2 halogen atoms or by a C₁-C₄ alkyl radical:    -   A group selected from among:-   R₁ represents hydrogen, a C₁-C₄ alkyl radical or a benzyl radical;-   n represents 0, 1, 2, 3 or 4;-   R₂ represents —NR₄R₅ or a group with formula:    Wherein the dotted line represents an optional chemical bond;-   R₃, R₄ y R₅ independently represent hydrogen or a C₁-C₄ alkyl;-   X, Y and Z independently represent hydrogen, fluorine, chlorine,    bromine, a C₁-C₄ alkyl, a C₁-C₄,alkoxy, a C₁-C₄ alkylthio,    trifluoromethyl, cyano, nitro and —NR₄R₅;-   W represents a bond between the two rings, CH₂, O, S and NR₄;-   m represents 0, 1, 2, 3 or 4:-   with the condition that when m=0, A is a substituted phenyl;-   or one of its physiologically acceptable salts.

The alkyl term C₁-C₄ represents a linear or branched carbonated chainincluding 1 to 4 atoms of carbon, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and terc-butyl.

Compounds object of the present invention that correspond to the aboveformula can be selected from among:

-   [1]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [2]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide.-   [3] Hydrochloride    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide.-   [4]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-3,5-dichlorobenzenesulphonamide.-   [5]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide.-   [6]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chlorothiophene-2-sulphonamide.-   [7]    N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [8]    N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide.-   [9]    N-[3-(2-dimethylamino-ethyl)-1H-indol-5-yl]-6-chloroimidazo[2,1-b]thiazol-5-sulphonamide.-   [10]    N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [11]    N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide    hydrochloride.-   [12]    N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide.-   [13]    N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide    hydrochloride.-   [14]    N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chlorothiophene-2-sulphonamide.-   [15]    N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide.-   [16]    N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulphonamide.-   [17]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide.-   [18]    N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide.-   [19]    N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [20]    N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-(2-pyridil)thiophene-2-sulphonamide.-   [21] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-2,1,3-    benzothiadiazol-4-sulphonamide.-   [22]    N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]quinoline-8-sulphonamide.-   [23]    N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalene-2-sulphonamide.-   [24]    N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-4-phenoxybenzenesulphonamide.-   [25]    N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide.-   [26]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethyl-naphthalene-2-sulphonamide.-   [27]    N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [28]    N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}naphthalene-1-sulphonamide.-   [29]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide.-   [30]    N-[3-dimethylaminomethyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [31]    N-[3-(2-dipropylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide.-   [32]    N-[3-(2-dipropylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [33]    N-[3-(2-dibutylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [34]    N-[3-(2-dibutylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide.-   [35]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalene-1-sulphonamide.-   [36]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-trans-β-styrenesulphonamide.-   [37]    N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-trans-β-styrenesulphonamide.-   [38]    N-[3-(octahydroindolizin-7-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [39]    N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-6-chloroimidazo[2,1-b]thiazol-5-sulphonamide.-   [40]    N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}naphthalene-2-sulphonamide.-   [41]    N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-α-toluenesulphonamide.-   [42]    N-[3-(3-diethylaminopropyl)-1H-indol-5-yl]naphthalene-2-sulphonamide.-   [43]    N-[3-(3-diethylaminopropyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [44]    N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide.-   [45]    N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}naphthalene-1-sulphonamide.-   [46]    N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}naphthalene-2-sulphonamide.-   [47]    N-[3-(2-dipropylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide.-   [48]    N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalene-1-sulphonamide.-   [49]    N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide.-   [50]    N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}quinoline-8-sulphonamide.-   [51]    N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}4-phenylbenzenesulphonamide.-   [52]    N-[3-(4-methylpiperazin-1-yl)ethyl-1H-indol-5-yl]naphthalene-2-sulphonamide.-   [53]    N-[3-(4-methylpiperazin-1-yl)ethyl-1H-indol-5-yl]-5-chloronaphthalene-1-sulphonamide.

The present invention also relates to the physiologically acceptablesalts of the compounds with the general formula (I), particularly theaddition salts of mineral acids such as hydrochloric, hydrobromic,phosphoric, sulphuric, nitric acids, and of organic acids such ascitric, maleic, fumaric, tartaric acids or their derivatives,p-toluensulphonic acid, methansulphonic acid, camphorsulphonic acid,etc.

The new derivatives with the general formula (I), wherein R₁, R₂, R₃,R₄, n and A are as indicated above, can be prepared according to thefollowing methods:

Method A

By reacting a compound with the general formula (II) or one of itssuitably protected derivatives

wherein A is as indicated previously in the general formula (I) and X isan acceptable salient group including a halogen atom, particularlychlorine:with a 5-aminoindol with the general formula (III), or one of itssuitably protected derivatives;

wherein n, R₁, R₂ and R₃ are as indicated previously in the generalformula (I); in order to obtain the corresponding sulphonamide and,optionally, eliminating from it the protective groups and/or forming apharmacologically acceptable salt.

The reaction between the compounds with the general formula (II) and(III) is carried out in the presence of an organic solvent such as analkyl ether, particularly diethyl ether, or a cycloalkyl, particularlytetrahydrofurane or dioxane, a halogenated organic hydrocarbon,particularly methylene chloride or chloroform, an alcohol, particularlymethanol or ethanol, an aprotic dipolar solvent, particularlyacetonitryl, pyridine or dimethylformamide, or any other suitablesolvent.

The reaction preferably is carried out in the presence of a suitableinorganic base such as hydroxides and carbonates of alkali metals, or inthe presence of an organic base, particularly triethylamine or pyridine.

The most suitable reaction temperatures range from 0° C. to ambienttemperature, and the reaction time is between 5 minutes and 24 hours.

The resulting sulphonamide can be isolated by evaporating the solvent,adding water and eventually adjusting the, pH so that it is obtained asa solid that can be isolated by filtration; or it can be extracted by asolvent immiscible in water such as chloroform and purified bychromatography or recrystallisation from a suitable solvent.

The compounds with the general formula (II) are commercially availableor can be prepared according to standard methods or by methods analogousto those described in the literature [E. E. Gilbert, Synthesis, 1969, 1,3] and the compounds with the general formula (III) can be preparedaccording to standard methods or by methods analogous to those describedin the literature [J. E. Macor, R. Post and K. Ryan, Synt Comm., 1993;23, 1, 65-72.; J. Guillaume, C. Dumont, J. Laurent and N. Nédélec, Eur.J. Med. Chem., 1987, 22, 33-43; M. L. Saccarello, R. Stradi, Synthesis,1979, 727].

Method B

The compounds with the general formula (I), wherein R₁, R₂, R₄, n and Aare as indicated above and R₃ represents a C₁-C₄ alkyl, can be preparedby alkylation of a compound with the general formula (I; wherein R₁, R₂,R₄, n and A are as indicated above and R₃ represents an atom ofhydrogen, with an alkyl halogenide or a dialkyl sulphate.

The reaction preferably is carried out in the presence of a suitablebase such as hydroxides and carbonates of alkali metals, metal hydrides,alkoxides such as sodium methoxide or potassium terbutoxide,organometallic compounds such as butyl lithium or terbutyl lithium, inthe presence of an organic solvent such as an alkyl ether, particularlydiethyl ether, or cycloalkyl, particularly tetrahydrofurane or dioxane,a hydrocarbon, particularly toluene, an alcohol, particularly methanolor ethanol, an aprotic dipolar solvent, particularly acetonitryl,pyridine or dimethylformamide, or any other suitable solvent. The mostsuitable temperatures are between 0° C. and the boiling point of thesolvent, and reaction times are between 1 and 24 hours.

The resulting sulphonamide can be isolated by concentrating the filtrateat reduced pressure, adding water and eventually adjusting the pH sothat it is obtained as a solid that can be isolated by filtration, or itcan be extracted with a solvent immiscible in water such as chloroformand purified by chromatography or recrystallisation from a suitablesolvent.

Method C

By condensation of a compound with the general formula (I) wherein R₁,R₃, and A are as indicated above, n=0 and R₂ represents an atom ofhydrogen, with a suitably substituted 4-piperidone the correspondingcompound is obtained with the general formula (I) wherein R₁, R₃, and Aare as indicated above, n=0 and R₂ represents a suitably substituted1,2,3,6-tetrahydropyridine-4-yl radical.

The reaction can take place in both an acid and a basic medium, in asuitable solvent at temperatures between 25 and 150° C.

Suitable basic conditions include inorganic bases such as sodium orpotassium hydroxide, or organic bases such as pyrrolidine ortriethylamine in solvents such as methanol or ethanol. Preferably,solutions of sodium methoxide in methanol at reflux. Reaction timesrange from 1 to 48 hours.

Suitable acidic conditions include hydrochloric acid in ethanol ortrifluoroacetic acid in acetic acid at temperatures between 50 and 100°C. and reaction times ranging from 1 to 48 hours.

The resulting sulphonamide can be isolated by dilution in water,eventually adjusting the pH, to obtain a solid that can be isolated byfiltration; or it can be extracted with a solvent immiscible in watersuch as chloroform and purified by chromatography or byrecrystallisation from a suitable solvent.

The compounds with the general formula (I) wherein R₁, R₃, and A are asindicated above, n=0 and R₂ represents an atom of hydrogen, can beprepared according to the method A from a 5-aminoindol.

Method D

The compounds with the general formula (I) wherein R₁, R₃, and A are asindicated above, n=0and R₂ represents a suitably substituted4-piperidinyl radical, can be prepared by reducing a compound with thegeneral formula (I) wherein R₁, R₃, and A are as indicated above, n=0and R₂ represents a suitably substituted 1,2,3,6-tetrahydropyridin-4-ylradical prepared according to the method C.

Hydrogenation takes place with the aid of a metallic catalyst such aspalladium, platinum or rhodium on a support such as carbon, aluminumoxide or barium sulphate, preferably palladium over carbon, with aninitial hydrogen pressure of between 1 and 10 atmospheres, preferablybetween 2 and 5 atmospheres, in a solvent such as methanol or ethanol.The reaction time ranges from 1 hour to 3 days.

The resulting sulphonamide can be isolated by filtering the catalyst andconcentrating the filtrate at reduced pressure. The product recoveredcan be used as is or it can be purified by chromatography or byrecrystallisation from a suitable solvent.

Method E

The pharmacologically acceptable salts of compounds with the, generalformula (I) can be conventionally prepared by reaction with a mineral,acid, such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitricacids or with organic acids such as, citric, maleic, fumaric, tartaricacids or their derivativesi p-toluensulphonic acid, methansulphonicacid, etc., in a suitable solvent such as methanol, ethanol, ethylether, ethyl acetate, acetonitryl or acetone and obtained with the usualtechniques of precipitation or crystallisation of the correspondingsalts.

During one of the synthesis sequences described, or in the preparationof the sintones used it may be necessary and/or desirable to protectsensitive or reactive groups in some of the molecules employed. This canbe performed by means of conventional protective groups such as thosedescribed in the literature [Protective groups in Organic Chemistry, edJ. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts,Protective Groups in Organic Chemistry, John Wiley & sons, 1991]. Theprotective groups can be eliminated in a suitable latter stage by knownmethods.

The invention provides pharmaceutical compositions that comprise, inaddition to an acceptable pharmaceutical excipient, at least onecompound with the general formula (I) or one of its physiologicallyacceptable salts. The invention also relates to the use of a compoundwith the general formula (I) and its physiologically acceptable salts inthe preparation of a medicament having 5-HT₆ serotonin receptorantagonistic activity, useful for preventing or treating variousdisorders of the Central Nervous System, and particularly anxiety,depression, cognitive memory disorders and senile dementia processes,and other dementias in which predominates a cognition deficit, psychosisinfant hyperkinesia (ADHD, attention deficit/hyperactivity disorder) andother disorders mediated by the 5-HT₆ serotonin receptor in mammals,including man.

The following examples show the preparation of novel compounds accordingto the invention. Also described in the affinity for the receptor 5HT₆of serotonin, as well as galenic formulae applicable to the compoundsobject of the invention. The examples provided below are provided forpurposes of illustration only and are in no way meant as a definition ofthe limits of the invention.

Method A

EXAMPLE 7 Preparation ofN-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulphonamide

To a solution of 3.05 g (15 mMol) of5-amino-3-(2-dimethylaminoethyl)-1H-indol in 100 ml of pyridine is addeddropwise at ambient temperature a solution of 4.21 g (15 mMol) of5-chloro-3-methyl-benzo[b]thiophene-2-sulphonyl chloride in 20 ml ofpyridine. The reaction mixture is stirred at ambient temperature for 20hours. It is then evaporated to dryness, slightly alkalinised withdiluted ammonia and dissolved in ethyl acetate. The organic phase iswashed with water and a saturated solution of sodium bicarbonate, it isseparated and dried with anhydrous sodium sulphate. The organic solutionis evaporated to dryness and the resulting solid is repeatedly washedwith ethyl ether, to yield 5.5 g (82%) ofN-[-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulphonamideas a solid with m.p. 226-227° C.

Method B

EXAMPLE 26 Preparation ofN-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethyl-naphthalene-2-sulphonamide

To a mixture of 285 mg (0.7 mMol) ofN-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide(example 17) and 80 mg (0,7 mMol) of potassium t-butoxide in 3 ml ofDMSO are stirred for 30 minutes at ambient temperature. Then are added105 mg (0.7 mMol) of ethyl iodide and left with stirring for 3 hours.Water is added and is extracted with ethyl acetate. The organic solutionis evaporated to dryness and the resulting crude is purified bychromatography on silica gel, using as an eluent mixtures of methylenechloride/methanol/ammonia, yieldingN-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethyl-naphthalene-2-sulphonamideas a solid with m.p. 49-50° C.

Method C

EXAMPLE 18 Preparation ofN-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide

To a solution of 712 mg (13.2 mMol) of sodium methoxide in 100 ml ofmethanol are added 850 mg (2.64 mMol) ofN-[1H-indol-5-yl]naphthalene-1-sulphonamide followed by 596 mg (5.28mMol) of 1-methyl-4-piperidone and the resulting solution is heated toreflux for 48 hours. The reaction mixture is concentrated at reducedpressure and the residue obtained is purified by chromatography oversilica gel, using as eluent mixtures of methylenechloride/methanol/ammonia, to yield 573 mg (52%) ofN-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamideas a solid with m.p. 244-245° C.

Method D

EXAMPLE 12 Preparation ofN-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide

To a solution of 417 mg (1 mMol) ofN-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamidein 50 ml of methanol are added 100 mg of 5% palladium on carbon. Themixture is hydrogenated at ambient temperature at an initial hydrogenpressure of 3 atmospheres for 20 hours. The reaction mixture is filteredand the filtrate is concentrated at reduced pressure to provide a crudethat is suspended in ethyl ether, yielding 272 mg (65%) ofN-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamideas a solid with m.p.=254-256° C.

Method E

EXAMPLE 3 Preparation ofN-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamidehydrochloride

1.05 g (2.5 mMol)-ofN-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide(example 2) are dissolved in 10 ml of ethanol and 0.6 ml are added of a4.2 N solution of hydrochloric acid in ethanol. It is allowed tocrystallise at ambient temperature.N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamidehydrochloride is obtained as a solid with m.p.=255-257° C.

The melting point and spectroscopic data for identifying some of thecompounds object of the present invention are shown in the followingtable:

Ex R₁ R₂ n R₃ A Salt m.p. ′C. IR cm¹ ¹H-RMN (300 MHz), δ (solvent) 1 H(CH₃CH₂)₂N— 2 H

— 170-173 3387, 2970, 2931, 1466, 1236, 1158, 1107, 1080, 993, 862, 805,657, 565. 0.88(t, 6H, J=7.1 Hz); 2.28(s, 3H); 2.30-2.46(m, 6H); 2.58(m,2H); 6.85(dd, 1H, J=8.6, 2.0 Hz); 7.10(m, 2H; 7.20(d, 1H, J=8.6 Hz);7.50(dd, 1H, J=8.7, 2.0 Hz); 7.90(d, 1H, J=2.0 Hz); 7.98(d, 1H, J=8.7Hz); 10.10 (bb, 1H); 10.80(s, 1H). (DMSO-d6) 2 H (CH₃CH₂)₂N— 2 H

— 170 3451, 3337, 2972, 1466, 1319, 1237, 1157, 1132, 1091, 991, 770,675, 583, 481. 0.90(t, 6H, J=7.1 Hz); 2.33-2.55(m, 8H); 6.69(dd, 1H,J=8.7, 1.8 Hz); 6. 95(s, 1H); 7.02(d, 1H, J=1.8Hz); 7.05(d, 1H, J=8.7Hz); 7.47(t, 1H, J=7.7 Hz0; 7.63(m, 1H); 7.70(m, 1H); 8.01(m, 2H);8.12(d, 1H, J=7.5 Hz); 8.77(d, 1H, J=8.1 # Hz); 10.10(bb, 1H); 10.66(s,1H) (DMSO-d6) 3 H (CH₃CH₂)₂N— 2 H

HCl 255-257 3378, 3065, 2558, 2489, 1460, 1317, 1162, 1143, 1131, 811,687, 602, 588. 1.22(t, 6H, J=7.2 Hz); 2.91-3.18(m, 8H); 6.65(d, 1H,J=8.6 Hz); 7.08(d, 1H, J=8.6 Hz); 7.17 (s, 1H); 7.20(d,1H, J=1.8 Hz);7.54(t, 1H, J=7.8 Hz); 7.63(m, 1H); 7.70(m, 1H); 8.03(d, 1H, J=7.8 Hz);8.08(d, 1H, J=7.1 Hz); 8.14(d, # 1H, J=8.2 Hz); 8.79(d, 1H, J=8.2 Hz);8.79(d, 1H, J=8.4 Hz); 10.26(s,1H); 10.90(bb, 1H); 11.01(s, 1H).(DMSO-d6) 4 H (CH₃CH₂)₂N— 2 H

— 168-170 3309, 3047, 2974, 1566, 1467, 1235, 1167, 1143, 1116, 1001,910, 799, 672, 587. 0.95(t, 6H, J=7.1 Hz); 2.44-2.58(m, 6H); 2.66(m,2H); 6.79(dd, 1H, J=8.6, 1.7 Hz); 7.08(d, 1H, J=0.9Hz); 7.13(d, 1H,J=1.7); 7.23(d, 1H, J=8.6 Hz); 7.58 (m, 2H); 7.87(m, 1H); 9.95(bb, 1H);10.82(s, 1H). (DMSO-d6) 5 H (CH₃CH₂)₂N— 2 H

— 161-163 3387, 2971, 1323, 1157, 1095 765, 670, 590 0.89(t, 6H, J=7.1Hz); 2.32-2.55(m, 6H); 2.62(m, 2H); 6.85(d, 1H, J=8.6 Hz); 7.08(d, 1H,J=2.0 Hz); 7.13(s, 1H); 7.18(d, 1H, J=8.6 Hz); 7.33-750 (m, 3H); 7.64(d,2H, J=7.5 Hz); 7.72(sys AB, 2H, J=8.6 Hz); 7.78(sys AB, 2H, J=8.6Hz);9.80(bb, 1H); 10.75(s, 1H). (DMSO-d6) 6 H (CH₃CH₂)₂N— 2 H

— 180-181 3375, 2978, 1467, 1417, 1236, 1212, 1115, 994, 624. 0.96(t,6H, J=7.1 Hz); 2.52(m, 4H); 2.57(m, 2H); 2.66(m, 2H); 6.83(dd, 1H,J=8.6, 1.9 Hz); 7.11(d, 1H, J=4.0 Hz); 7.14(d, 1H, J=1.9 Hz); 7.17(d,1H, J=1.9 Hz); 7.20-7.24(m, 2H); 10.01(bb 1H); 10.81(s, 1H). (DMSO-d6) 7H (CH₃)₂N— 2 H

— 226-227 3422, 3238, 1332, 1155, 1114, 1079, 986, 861, 803, 655, 564.2.04(s, 6H); 2.23(m, 2H); 2.28(s, 3H), 2.59(m, 2H); 6.83(dd, 1H, J=8.4,1.5 Hz); 7.09 (s, 2H); 7.19(d, 1H, J=8.4 Hz); 7.49(dd, 1H, J=8.7, 1.6Hz); 7.91(d, 1H, J=1.6 Hz); 7.99(d, 1H, J=8.7 Hz); 10.13(bb, 1H), 10.79(s, 1H) (DMSO-d6) 8 H (CH₃)₂N— 2 H

— 203-205 3357, 1475, 1282, 1157, 1127, 990, 957, 809,773,613,587,557,498. 2.09(s, 6H); 2.21(m, 2H); 2.54(m, 2H); 6.69(dd, 1H, J=8.6,1.7 hz); 6.94 (s, 1H); 7.03 (s, 1H); 7.06(d, 1H, J=8.1 Hz0, 7.49(t, 1H,J=7.8 Hz); 7.64(m, 1H); 7.71(m, 1H); 8.02 (m, 2H); 8.13(d, 1H, J=8.1Hz); 8.79(d, 1H, J=8.4 Hz); 10.10(bb, 1H); 10.68(s, 1H) (DMSO-d6) 9 H(CH₃)₂N— 2 H

— 215 (desc) 3247, 3094, 1467, 1272, 1261, 1230, 625 2.17(s, 6H);2.36(m, 2H); 2.65(m,2 H); 6.77(dd, J=8.6, 1.7 Hz, 1H); 7.07(s, 1H);7.09(s, 1H); 7.18(d, J=8.6 Hz,1 H); 7.51(d, J=4.5 Hz, 1H); 7.81(d, J=4.5Hz, 1H); 10.80 (s, 1H). (DMSO- d6). 10 H

0 H

— 250 (desc) 3407, 2390, 1466, 1334, 1156, 113, 1080, 651, 565.1.53-1.80(m, 4H); 2.26(s, 3H); 2.39-2.71(m, 6H); 3.02(d, 2H, J=8.8 Hz);6.76(d, 1H, J=8.8 Hz); 7.05(s, 1H); 7.11(s, 1H); 7.19(d, 1H, J=8.8 Hz);7.51(d, 1H, J=8.7 Hz); 7.91(s, 1H); 8.00(d, 1H, J=8.7 Hz); 10.10(bb,1H); 10.90(s, 1H). (DMSO-d6) 11 H

0 H

HCl 220 (desc) 3423, 3214, 3043, 2942, 2688, 1464, 1317, 1149, 1114,1080, 748, 670, 589. 1.75-1.92(m, 4H); 2.31(s, 3H); 2.66(s, 3H); 2.80(m,1H); 2.95(m, 2H); 3.24(d, 2H, J=11.4 Hz); 6.76(d, 1H, J=8.7 Hz); 7.07(s,1H); 7.19(m, 2H); 7.50(d, 1H, J=8.6 Hz); 7.93(s, 1Hz); 8.01(d, 1H, J=8.6Hz); 8.34 (s, 1H); 10.90(bb, 1H); 11.01(s, 1H). (DMSO-d6) 12 H

0 H

— 54-256 3343, 2938, 2929, 1470 1154, 1121, 1108, 988, 947, 805, 769,589. 1.49(m, 2H); 1.61(m, 2H); 2.14(m, 2H); 2.30(s, 3H); 2.40(m, 1H);2.90(d, 2H, J=10.6 Hz); 6.65(d, 1H, J=8.6 Hz); 6.90(s, 1H); 6.96(s, 1H);7.05(d, 1H, J=8.6 Hz); 7.46(dt, 1H, J=7.51, 1.83 Hz); 7.46(m, 1H);7.71(m, 1H); 7.99(d, 1H, J=8.6 Hz); 8.03(d, 1H, J=8.6 Hz); 8.12(d, 1H, #J=8.2 Hz); 8.77(d, 1H, J=8.12(d, 1H, J=8.2 Hz); 8.77(d, 1H, J=8.6 Hz);10.07(bb, 1H); 10.71(s, 1H). (DMSO-d6) 13 H

0 H

HCl 212 (desc) 3423, 3269, 3114, 2955, 2733, 1469, 1321, 1155, 1133,947, 769. 1.80(M, 4H); 2.74(m, 4H); 3.04(m, 2H); 3.39(m, 2H); 6.63(d,1H, J=8.6 Hz); 7.00(s, 2H); 7.08(d, 1H, J=8.6 Hz); 7.49(t, 1H, J=7.7Hz); 7.60-7.77(m, 2H); 8.04(d, 2H, J=7.5 Hz); 8.13(d, 1H, J=8.2 Hz);8.79(d, 1H, J=8.2 Hz); 10.16(bb, 1H); 10.88(s, 1H). (DMSO-d6) 14 H

0 H

— 284 (desc) 3371, 2943, 1468, 1410, 1324, 1148, 993, 604. 1.62(m, 2H);1.78(d, 2H, J=11.7 Hz); 1.99(m, 2H); 2.18(s, 3H); 2.55(m, 1H); 2.84(d,2H, J=10.6 Hz); 6.81(d, 1H, J=8.6 Hz); 7.07(s, 1H); 7.13(m 1H); 7.16(s,1H); 7.20-7.26 (m, 1H); 9.90 (bb, 1H); 10.83(s,1H). (DMSO-d6) 15 H

0 H

— 247-248 3361, 2936, 1318, 1155, 1095, 767, 670, 587. 1.52(s, 2H);1.67(m, 2H); 1.85(m, 2H) 2.08(s, 3H); 2.44(m, 1H); 2.67(d, 2H, 10.25Hz); 6.83(d, 1H, J=8.4 Hz); 7.01(s, 1H); 7.03(s, 1H); 7.19(d, 1H, J=8.4Hz); 7.35-7.50(m, 3H); 7.63-7.73(m, 4H); 7.79(sys AB, 2H, J=7.6 Hz);9.71(bb, 1H); 10.76(s, 1H) (DMSO-d6). 16 H

0 H

— 280 (desc) 3398, 3257, 2933, 1161, 1143, 789, 589. 1.25-1.52(m, 4H);1.885(m, 2H); 2.18(s, 3H); 2.27(m, 1H); 2.74 (d, J=11.4 Hz, 2H);6.72(dd, J=8.6, 2.0 Hz, 1H); 6.83(d, J=1.5 Hz, 1H); 6.90(d, J=2.0 Hz,1H); 7.02(d, J=8.6 Hz, 1H); 7.57(m, 1H); 7.74(dd, J=8.4, 4.3 Hz, 1 H);8.12 (dd, J=7.3, 1.3 Hz, 1H); 8.19(dd, J=8.2, 1.3 Hz, 1H); 8.52(dd,J=1.7 Hz, 1H); 9.21(dd, # J=4.3, 1.7 Hz, 1H); 9.36(s, 1H); 10.64(s, 1H).(DMSO-d6). 17 H (CH₃CH₂)₂N— 2 H

— 172-173 3319, 2970, 2930, 2870, 1327,1153, 1130, 1110, 1075, 956, 676,658, 551, 476. 0.87(t, J=7.1 Hz, 6H); 2.39(m, 6H); 2.55(m, 2H); 6.82(d,J=8.6 Hz, 1H); 7.05 (s, 1H); 7.09(s, 1H); 7.13(d, J=8.6 Hz, 1H); 7.60(m,2H); 7.73 (d, J=8.6Hz, 1H); 7.95(d, J=7.9 Hz, 1H) 8.01 (m, 2H); 8.26 (s,1H); 9.86(bb, 1 H); 10.71(s, 1H). (DMSO-d6). 18 H

0 H

— 244-245 (desc) 3346, 2943, 1474, 1283, 1261, 1156, 1123, 801, 771 589,503. 2.25(s, 3H); 2.31(m, 2H); 2.46(m, 2 H); 2.90(m, 2H); 5.34(s, 1H);6.78(dd, J=8.6, 2.0 Hz, 1H); 7.09(d, J=1.5 Hz, 1 H); 7.14 (d, J=8.6 Hz,1H); 7.25(d, J=2.0 Hz, 1H); 7.49(t, J=7.8 Hz, 1H); 7.66(m, 1H); 7.75(m,1H); 8.04(m, 2H); 8.14(d, J=8.2 Hz, 1H; 8.83(d, J=8.6 Hz, # 1H);10.14(bb, 1H); 11.03(s, 1H). (DMSO-d). 19 H

1 H

— 230 (desc) 2796, 1452, 1316, 1149, 1114, 1080, 1001, 810, 646, 559.1.80-2.26(m, 8H); 2.04(s, 3H); 2.30(s, 3H); 3.41(s, 2H); 6.89(dd, J=8.6,1.56 Hz, 1H); 7.16(s, 1H); 7.22(d, J=8.6 Hz 1H; 7.29(s, 1H); 7.49(dd,J=8.7, 1.7 Hz, 1H); 7.90(d, J=1.7 Hz, 1H); 7.98(d, J=8.7 Hz, 1H);10.13(bb, 1H); 10.93(s, 1H) (DMSO-d6). 20 H (CH₃)₂N— 2 H

— 209-211 3377, 2951, 2798, 1469, 1429, 1321, 1158, 777, 594. 2.05(s,6H); 2.32(m, 2H); 2.65(m, 2 H); 6.86(dd, J=8.6, 1.8 Hz, 1H); 7.10(d,J=1.8 Hz, 1H); 7.18(d, J=1.8 Hz, 1H); 7.21 (d, J=8.6 Hz, 1H); 7.32(dd,J=7.5, 4.6 Hz, 1H); 7.36(d, J=3.9 Hz, 1H); 7.71(d, J=3.9 Hz, 1H);7.83(m, 1H); 7.93(m, 1H); 8.49(d, J=4.6 Hz, 1H); 9.97(bb, 1H); #10.79(s, 1H). (DMSO-d6). 21 H (CH₃)₂N— 2 H

— 192 3321, 2949, 1474, 1327, 1152, 1138, 1104, 981, 614. 2.10(s, 6H);2.21(m, 2H); 2.56(m, 2 H); 6.72(d, J=8.6 Hz, 1H); 6.96(s, 1H); 7.03 (s,1H); 7.07(d, J=8.6 Hz, 1H); 7.70(m, 1H); 8.07(d, J=7.0 Hz, 1H); 8.29 (d,J=8.8 Hz, 1H); 10.14(bb, 1H); 10.69(s, 1H). (DMSO-d6). 22 H (CH₃)₂N— 2 H

— 250 (desc) 3252, 2857, 1459, 1426, 1333, 1161, 1144, 789, 680, 589.2.07(s, 6H); 2.16(m, 2H); 2.51(m, 2 H); 6.73(dd, J=8.6, 1.8 Hz, 1H);6.94(s, 1H) 6.99(s, 1H); 7.02(d, J=8.6 Hz, 1 H); 7.59(t, J=7.8 Hz, 1H);7.73(dd, J=8.4, 4.1 Hz, 1H); 8.18(m, 2H); 8.50(dd, J=8.4, 1.5 Hz, 1H);9.20(dd, J=4.1, 1.5 Hz, 1H); 9.45(bb, 1H); 1064(s, 1H). (DMSO-d6). 23 H(CH₃)₂N— 2 H

— 230-240 (desc) 3404, 2944, 2918, 2855, 1465, 1332, 1157, 1140, 1080,650, 639, 526. 2.01(s, 6H); 2.18(m, 2H); 2.57(m, 2 H); 681 (dd, J=8.6,1.7 Hz, 1H); 7.02 (s,1H); 7.05(d, J=1.7 Hz, 1H); 7.15(d, J=8.6 Hz, 1H);7.57(m, 1H); 7.82(d, J=7.5 Hz, 1H); 7.91(d, J=8.9 Hz, 1H); 8.06(d, J=8.2Hz, 1H); 8.29(d, J=8.9 Hz, 1H); 8.35(s, 1H); # 9.94(bb, 1H); 10.74(s,1H). (DMSO-d6). 24 H (CH₃)₂N— 2 H

— 152-154 3232, 2862, 2827, 2785, 1583, 1488, 1333, 1248, 1155, 1091755, 693, 571, 541. 2.16(s, 6H); 2.37(m, 2H); 2.66(m, 2 H); 6.80(d,J=8.6 Hz, 1H); 6.96-7.12(m, 6H); 7.14-7.25(M, 2H); 7.41(m, 2H); 7.64(dd,J=8.5, 1.9 Hz, 2 (DMSO-d6). 25 H (CH₃)₂N— 2 H

— 184-186 3451, 3388, 2950, 2775, 1466, 1322, 1159, 1095, 763, 670, 591.2.08(s, 6H); 2.32(m, 2H); 2.64(m,2 H); 6.83(dd, J=8.6, 1.9 Hz, 1H);7.08(d, J=2.0 Hz,1H); 7.11(d, J=1.9 Hz, 1H); 7.17(d, J=8.6 Hz,1H);7.34-7.50(m, 3H); 7.66(d, J=7.5 Hz, 2H); 7.72(AB sys, J=8.6 Hz, 2H);7.79(AB sys, J=8.6 Hz, 2H); 9.79(s, 1H); 10.75(s, 1H). (DMSO-d6). 26 H(CH₃CH₂)₂N— 2 Et

— 49-50 3386, 2970, 2931, 1474, 1337, 1167, 1151, 1130, 1073, 661, 5500.82(t, J=7.0 Hz, 6H); 0.98(t, J=7.0 Hz, 3H); 2.37(q, J=Hz, 4H);2.49(m,2 H); 2.54(m, 2H); 3.66(q, J=7.1 Hz, 2H) 6.37 (dd, J=8.61, 1.6Hz, 1H); 6.98(s, H); 7.17 (d, J=1.6 Hz, 1H); 7.26(d, J=8.61 Hz, 1H);7.56-7.72 (m, 3H); 7.99-8.11(m, 3H); 8.26 (s, 1H); 10.97(s, 1H).(DMSO-d6). 27 H

2 H

— 200-201 3366, 2951, 2816, 1460, 1421, 1319, 1283, 1157, 1114, 1078,865, 651, 561 2.25(m, 6H); 2.27(s. 3H); 2.62(t, J=7.9 Hz, 2H); 3.52(m,4H); 6.84(d, J=8.2 Hz, 1H); 7.06(s, 1H); 7.10(s, 1H); 7.20(d, J=8.6 Hz,1H); 7.50(d, J=8.6 Hz, 1H); 7.92(s, 1H); 8.00 (d, J=8.6 Hz, 1H);10.13(s, 1H); 10.80(s, 1H) (DMSO-d6) 28 H

2 H

— 218-220 3389, 3152, 2916, 2819, 1466, 1313, 1157, 1129, 1108, 771, 5872.30(m, 6H); 2.56(m, 2H); 3.56(m, 4H); 6.69(d, J=8.4 Hz, 1H); 6.93(s,1H); 7.06(m, 2H); 7.48(t, J=7.3 Hz, 1H); 7.67(m, 2H); 8.02(m, 2H); 8.13(d, J=8.1 Hz, 1H); 8.78 (d, J=8.1 Hz, 1H); 10.10(s, 1H); 10.68(s, 1H).(DMSO-d6) 29 H (CH₃CH₂)₂N— 2 CH₃

— 134-136 2968, 2930, 1488, 1329, 1159, 1131, 1074, 660, 550 0.98(t,J=7.1 Hz, 6H); 2.55(M, 6H); 2.70(m, 2H); 3.67(s, 3H); 6.84 (s, 1H);6.93(dd, J=8.6, 2 Hz, 1H); 7.41(d, J=8.7 Hz, 1H); 7.18(d, J=7.1 Hz, 1H);7.26(S, 1H) 7.57 (m, 2H); 7.67(dd, J=8.7, 1.8 Hz; 7.84(m, 3H); 8.27(d,J=1.7 Hz, 1H). (DMSO-d6) 30 H (CH₃)₂N— 1 H

— 148-152 3398, 2930, 1467, 1158, 1113, 1079, 861, 803, 651 561. 1.89(m,6H); 2.29(s, 3H); 2.48(s, 2H); 6.83(m, 1H); 7.18(m, 3H); 7.50(m, 1H);7.91(m, 1H); 8.00 (m, 1H); 10.13(b, 1H) 10.92(s, 1H). (DMSO-d6) 31 H(CH₃CH₂CH₂)₂N— 2 H

— 76-80 3399, 2959, 2931, 1466, 1159, 1132, 802, 770, 588 0.82(t, J=6.7Hz, 6H); 1.34(q, J=6.71 Hz, 4H); 2.31(m, 4H); 2.40(m, 2H); 2.52(m, 2H);6.69(d, J=8.6 Hz, 1H); 7.04(M, 3H); 7.47(M, 1H); 7.66(m, 2H); 8.02(m,2H); 8.11(d, J=8.1 Hz, 1H); 8.78(d, J=8.4 Hz, 1H); 10.12(s, 1H);10.67(s, 1H). (DMSO-d6) 32 H (CH₃CH₂CH₂)₂N— 2 H

— 90-95 3406, 2959, 2932, 2872, 1466, 1157, 1079, 861, 652, 561 0.80(t,J=7.3 Hz, 6H); 1.31(q, J=7.3 Hz, 4H); 2.26(m, 7H); 2.38(m, 2H); 2.56(m,2H); 6.83(dd, J=8.4, 1.8 Hz, 1H); 7.08(s, 2H); 7.20(d, J=8.6 Hz, 1H);7.50(dd, J=8.6, 2.0 Hz, 1H); 7.90(d, J=2.0 Hz, 1H); 7.99(d, J=8.6 Hz,1H); 10.12(b, 1H); 10.79(s, 1H). (DMSO-d6) 33 H (CH₃CH₂CH₂CH₂)₂N— 2 H

— 79-80 3398, 2956, 2930, 2870, 1466, 1158, 1080, 862, 801, 653, 5620.84(t, J=6.8 Hz, 6H); 1.24(m, 8H); 2.26(s, 3H); 2.28(m, 4H); 2.39(m,2H); 2.57(m, 2H); 6.82(dd, J= 8.6, 1.9 Hz, 1H); 7.09(d, J=1.8 Hz, 2H);7.18(d, J=8.6 Hz, 1H); 7.50(dd, J=8.6, 1.9 Hz, 1H); 7.89(d, J=1.8 Hz,1H); 7.98(d, J=8.6 Hz, 1H); # 10.14(b, 1H); 10.78(s, 1H). (DMSO-d6) 34 H(CH₃CH₂CH₂CH₂)₂N— 2 H

— 111-113 3291, 2955, 2926, 2870, 1327, 1158, 1136, 772, 676, 611, 5850.86(t, J=7.0 Hz, 6H); 1.29(m, 8H); 2.35(m, 4H); 2.41(m, 2H); 2.53(m,2H); 6.67(dd, J=8.5, 1.9 Hz, 1H); 7.09(m, 3H); 7.48(t, J=7.9 Hz, 1H);7.68(m, 2H); 8.01(s, 1H); 8.04(s, 1H); 8.12(d, J=8.2 Hz, 1H); 8.78(d,J=8.2 Hz, 1H); 10.13(s, 1H); 10.67(s, 1H). (DMSO-d6) 35 H (CH₃CH₂)₂N— 2H

— 154-156 3402, 2978, 1471, 1285, 1162, 1135, 1018, 780, 629, 6060.88(t, J=6.7 Hz, 6H); 2.41(m, 6H); 2.49(m, 2H); 6.71(d, J=8.1 Hz, 1H);6.88(S, 1H); 7.07(m, 2H); 7.66(m, 2H); 7.84 (d, J=7.0 Hz, 1H);8.09(d,J=7.0 Hz, 1H); 8.41(d, J=8.2 Hz, 1H); 8.79(d, J=8.6 Hz, 1H); 10.17(b,1H); 10.71(s, 1H). (DMSO-d6) 36 H (CH₃CH₂)₂N— 2 H

— 125-130 3404, 2972, 1473, 1319, 1142, 967, 745, 541 0.94(t, J=7.1 Hz,6H); 2.50(q, J=7.1 Hz, 4H); 2.59(m, 2H); 2.68(m, 2H); 6.94(dd, J=8.6,1.8 Hz, 1H); 7.26(m, 8H); 7.59(m, 2H); 9.54(b, 1H); 10.77(s, 1H).(DMSP-d6) 37 H

1 H

— 203 (desc) 2809, 1340, 1150, 746, 542 2.06(s, 3H); 2.22(m, 6H); 3.36(m2H); 3.49 (s, 2H); 6.95(dd, J=8.6, 1.8 Hz, 1H); 7.8(s, 2H); 7.24(m, 2H);7.37(m, 3H); 7.45(d, J=1.8 Hz, 1H); 7.61(m, 2H); 9.53(s, 1H); 10.90(s,1H). (DMSO-d6) 38 H

0 H

— 142-144 3413, 1466, 1270, 1237, 117, 986, 626 1.12(m, 3H); 1.81(m,9H); 2.22(s, 3H); 2.93(m, 2H); 6.84(dd, J=8.5, 1.7Hz, 1H; 6.99(s, 1H);7.03(s, 1H); 7.20(d, J=8.6 Hz, 1H); 7.52(dd, J=8.6, 2.0 Hz, 1H); 7.90(d,11.7 Hz, 1H); 8.00(d, J=8.6 Hz, 10.01)b, 1H); 10.61(s, 1H). (DMSO-d6) 39H (CH₃CH₂)₂N— 2 H

— 197-198 3338, 1466, 1270, 1237, 117, 986, 626 0.96(t, J=7.1 Hz, 6H);2.53(m, 6H); 2.63(m, 2H); 6.78(dd, J=8.5, 1.6 Hz, 1H); 7.10(s, 2H);7.18(d, J= 8.6Hz, 1H); 7.51(d, J=4.6 Hz, 1H); 7.80(d, J=4.6 Hz, 1H);10.78(s, 1H). (DMSO- d6) 40 H

2 H

— 85-90 3399, 3257, 2920, 2855, 2814, 1460, 1330, 1157, 1131, 1113,1074, 659, 551, 477 2.27(m, 6H); 2.61(t, J=7.9 Hz, 2H); 3.52, (t, J=4.6Hz, 4H); 6.82(dd, J=8.6, 2.0 Hz, 1H); 7.06(s, 1H); 7.07(s, 1H); 7.15(d,J=8.6 Hz, 1H); 7.61(m, 2H); 7.74(dd, J=8.8, 1.8 Hz, 1H); 7.96(d, J=8.1Hz, 1H); 8.03(m, 2H); 8.27 (s, 1H); 9.87(s, 1H); 10.74(s, 1H). (DMSO-d6)41 H

1 H

— 99-102 3398, 2934, 2806, 1458, 1331, 1127, 700, 542 2.11(s, 3H);2.32(m, 6H); 3.35(m, 2H), 3.56(s, 2H); 4.29(s, 2H); 6.98(d, J=8.2 Hz,1H); 7.29(m, 7H); 7.53(s, 1H); 9.40(s, 1H); 10.94(s, 1H). (DMSO-d6) 42 H(CH₃CH₂)₂N— 3 H

— 128-130 3259, 2973, 2939, 2827, 1468, 1332, 1159, 1131, 1075, 670, 5550.86(t, J=7.0 Hz, 6H); 1.51(t, J=6.9 Hz, 2H); 2.27(t, J=6.9 Hz, 2H);2.35(q, J=7.0 Hz, 4H); 2.46(m, 2H); 6.77(d, J=8.6 Hz, 1H); 7.00(s, 1H);7.10(m, 2H); 7.60(m, 2H); 7.72(d, J=8.8 Hz, 1H); 7.95(d, J=7.9 Hz, 1H);8.02(m, 2H); 8.26(s, 1H); 9.86 (b, 1H); 10.6(S, 1H). (DMSO-d6) 43 H(CH₃CH₂)₂N— 3 H

— 156-158 3247, 2969, 2938, 1467, 1340, 1159, 1113, 1080, 862, 666, 5580.88(t, J=7.0 Hz, 6H); 1.52(m, 2H); 2.29(m, 5H); 2.37(q, J=7.0 Hz, 4H);2.47(m, 2H); 6.81(dd, J=8.6, 1.5 Hz, 1H); 7.06(d, J=1.6 Hz, 1H); 7.12(d,J=1.5 Hz, 1H); 7.18(d, J=8.6 Hz, 1H); 7.51(dd, J=8.6, 2.0 Hz, 1H););7.91(d, J=2.0 Hz, 1H); 7.99(d, # J=8.6 Hz, 1H); 10.06(b, 1H). (DMSO-d6)44 H

2 H

— 201-203 3386, 2929, 1466, 1157, 1106, 1080, 992, 861, 650, 561 1.62(m,4H); 2.29(s, 3H); 2.30(m, 4H); 2.36(m, 2H); 6.86(d, J=8.6 Hz, 1H);7.05(s, 1H); 7.09(s, 1H); 7.21(dd, J=8.6, 2.2 Hz, 1H); 7.50(dd, J=8.7,2.0 Hz, 1H); 7.92(s, 1H); 7.99(dd, J=8.7, 2.2 Hz, 1H); 10.10(b, 1H);10.81(s, 1H). (DMSO-d6) 45 H

2 H

— 212-214 3354, 2964, 2812, 1466, 1201, 1157, 1124, 808, 773, 5931.66(m, 4H); 2.36(m, 6H); 2.58(m, 2H); 6.71(d, J=8.6 Hz, 1H; 6.93(s,1H); 7.02(s, 1H); 7.07(d, J=8.6 Hz, 1H); 7.48(m, 1H); 7.68(m, 2H);8.02(dd, J=7.2, 1.2 Hz, 2H); 8.12(d,=8.2 Hz, 1H); 8.79(d, J=8.6 Hz, 1H);10.10(B, 1H); 10.68(s, 1H). (DMSO-d6) 46 H

2 H

— 180-182 3375, 2968, 2821, 1467, 1323, 1313, 1146, 1139, 1131, 1079,972, 654, 549 1.60(m, 4H); 2.26(M, 4H); 2.26(m, 4H); 2.35(m, 2H);2.61(m, 2H); 6.82(dd, J=8.6, 2.0 Hz, 1H); 7.05(m, 2H); 7.14(d, J=8.6 Hz,1H); 7.61(m, 2H); 7.74(dd, J=8.6, 1.8 Hz, 1H); 7.95(d, J=7.9 Hz, 1H);8.02(m, 2H); 8.27(s, 1H); 9.86(b, 1H); 10.72(s, 1H). (DMSO-d6) 47 H(CH₃CH₂CH₂)₂N— 2 H

— 58-64 (desc) 3398, 3255, 2958, 2931, 2872, 1466, 1330, 1156, 1130,1074, 659, 551 0.79(t, J=7.3 Hz, 6H); 1.31(q, J=7.3 Hz, 4H); 2.28(t,J=7.3 Hz, 4H); 2.42(m, 2H); 2.57(m, 2H); 6.80(dd, J=8.6, 1.7 Hz,1H);7.04(d, J=1.7 Hz, 1H); 7.12(m 2H); 7.60(m, 2H);7.72(dd, J=8.6, 1.7Hz, 1H); 7.98(m, 3H); 8.25(s, 1H); 9.87(b, 1H); 10.70(s, 1H). (DMSO-d6)48 H (CH₃)₂N— 2 H

— 201-203 3369, 1473, 1161, 1125, 1017, 789, 619 2.06(s, 6H); 2.15(t,J=8.2 Hz, 2H); 2.52(t, J=8.2 Hz, 2H); 6.69(d, J=8.7 Hz, 1H); 6.85(s,1H); 7.02(s, 1H); 7.08(d, J=8.7 Hz, 1H); 7.67(m, 2H); 7.84(d, J=7.3 Hz,1H); 8.10(d, J=7.3 Hz, 1H); 8.41(d, J=8.4 Hz, 1H); 8.79(d, J=8.7 Hz,1H); 10.15(b, 1H); 10.70(s, 1H). (DMSO-d6) 49 H (CH₃)₂N— 2 H

— 180-190 3399, 3255, 2943, 1466, 1330, 1156, 1131, 1075, 659, 5502.03(s, 6H); 2.22(t, J=8.2 Hz, 2H); 2.58(t, J=8.2 Hz, 2H); 6.80(d, J=8.4Hz, 1H); 7.04(s, 1H); 7.07(s, 1H); 7.13(d, J=8.6 Hz, 1H0; 7.60(M, 2H);7.74(d, J=8.6 Hz, 1H); 7.95(d, J=7.7 Hz, 1H); 8.02(m, 2H); 8.26(s, 1H);9.86(b, 1H); 10.71(s, 1H). (DMSO-d6) 50 H

2 H

— 234-235 3400, 3279, 2913, 2852, 1464, 1420, 1315, 1163, 1118, 951, 5922.29(m, 6H); 2.54(m, 2H); 3.57(m, 4H); 6.72(d, J=8.1 Hz, 1H); 7.01(m,3H); 7.60(T, J=7.7 Hz, 1H); 7.74(d, J=8.4 Hz, 1H); 8.19(m, 2H); 8.52(d,J=8.4 Hz, 1H); 9.21(s, 1H); 9.44(s, 1H); 10.65(s, 1H). (DMSO-d6) 51 H

2 H

— 225-228 3340, 2857, 1479, 1324, 1153, 1116, 1094, 768, 670, 5882.29(m, 6H); 2.66(m, 2H); 3.47(m, 4H); 6.84(d, J=8.6 Hz, 1H); 7.07(s,1H); 7.09(s, 1H); 7.18(d, J=8.4 Hz, 1J); 7.45(m, 3H); 7.70(m, 4H);7.79(m, 2H, 9.79(s, 1H); 10.77(s, 1H). (DMSO-d6) 52 H

2 H

— 129-131 3367, 2924, 2852, 2799, 1465, 1311, 1154, 1130, 1077, 666, 5571.40-1.60(m, 4H); 1.83(m, 2H); 2.14(s, 3H); 2.36(m, 1H); 2.67(d, J=11.2Hz, 2H); 6.78(d, J=8.4 Hz, 1H); 6.97(s, 1H); 7.00(s, 1H); 7.12(d, J=8.6Hz, 1H; 7.50-7.68(m, 2H); 7.73(d, J=9.0 Hz, 1H); # 8.00(m, 3H); 8.23(s,1H); 9.78(B, 1H); 10.71(s, 1H). (DMSO-d6) 53 H

2 H

— 246-249 3329, 2940, 2916, 1470, 1158, 1125, 1110, 1015, 791, 5981.35-1.47(m, 4H); 1.86(m, 2H); 2.17(s, 3H); 2.28(m, 1H); 2.76(d, J=10.6Hz, 2H); 6.68(d, J=8.8 Hz, 1H); 6.75(s, 1H); 6.94(s, 1H); 7.08(d, J=9.0Hz, 1H); 7.60-7.73(m, 2H); 7.85(d, J=7.1 Hz, 1H); 8.06(d, J=7.1 Hz, 1H);8.40(d, J=7.9 Hz, 1H); 8.79(d, J=9.0 Hz, 1H); 10.20(b, 1H); 10.68(s,1H). (DMSO- d6)Biological AssaysBinding with Serotonin Receptor 5HT₆

Cell membranes of HEK-293 cells expressing the 5HT₆ human recombinantreceptor were supplied by Receptor Biology. In said membranes thereceptor concentration is 2.18 pmol/mg protein and the proteinconcentration is 9.17 mg/ml. The experimental protocol follows themethod of B. L. Roth et al. [B. L. Roth, S. C. Craigo, M. S. Choudhary,A. Uluer, F. J. Monsma, Y. Shen, H. Y. Meltzer, D. R. Sibley: Binding ofTypical and Atypical Antipsychotic Agents to 5-Hydroxytryptamine-6 andHydroxytriptamine-7 Receptors. The Journal of Pharmacology andExperimental Therapeutics, 1994, 268, 1403] with slight changes. Thecommercial membrane is diluted (1:40 dilution) with the binding buffer:50 mM Tris-HCl, 10 mM MgCl₂, 0.5 mM EDTA (pH 7.4). The radioligand usedis [³H]-LSD at a concentration of 2.7 nM with a final volume of 200 μlincubation is initiated by adding 100 μl of membrane suspension, (≈22.9μg membrane protein), and is prolonged for 60 minutes at a temperatureof 37° C. The incubation is ended by fast filtration in a Brandel CellHarvester through fiber glass filters made by Schleicher & Schuell GF3362 pretreated with a solution of polyethylenimine at 0.5%. The filtersare washed three times with three milliliters of buffer Tris-HCl 50 mMpH 7.4. The filters are transferred to flasks and 5 ml of Ecoscint Hliquid scintillation cocktail are added to each flask. The flasks areallowed to reach equilibrium for several hours before counting with aWallac Winspectral 1414 scintillation counter. Non-specific binding isdetermined in the presence of 100 μM of serotonin. Tests were made intriplicate. The inhibition constants (K_(i), nM) were calculated bynon-linear regression analysis using the program EBDA/LIGAND [Munson andRodbard, Analytical Biochemistry, 1980, 107, 220]. The following tableshows results indicative of binding for some of the compounds object ofthe present invention. TABLE % Inhibition Example 10⁻⁶ M K_(I) (nM) 198.1 ± 4.0 0.28 3 96.6 ± 5.2 3.5 4 96.2 ± 0.6 9.3 5 101.2 ± 0.1  1.0 697.6 ± 1.8 8.7 7 103.0 ± 7.9  0.13 8 94.5 ± 7.0 0.76 9 96.8 ± 3.7 2.2 11101.3 0.98 13 98.3 4.7 14 95.7 ± 3.4 24.3 15 97.4 ± 0.8 6.8 16 94.4 ±8.6 21.2 17 102.0 5.3

The daily doses in human medicine are between 1 milligram and 500milligrams of product, which can be given in one or moreadministrations. The compositions are prepared in forms compatible withthe administration means used, such as sugar-coated pills, tablets,capsules, suppositories, solutions or suspensions. These compositionsare prepared by known methods and comprise between 1 and 60% by weightof the active principle (compound with the general formula 1) and 40 to99% by weight of a suitable pharmaceutical vehicle compatible with theactive principle and the physical form of the composition used. By wayof example, the formula of a tablet containing a product of theinvention is shown. Example of formula per tablet: Example 1 5 mgLactose 60 mg  Crystalline cellulose 25 mg  K 90 Povidone 5 mgPregelatinised starch 3 mg Colloidal silicon dioxide 1 mg Magnesiumstearate 1 mg total weight per tablet 100 mg 

1. A process for preparing a derivative of sulphonamide with the generalformula (I)

wherein A represents a substituent selected from among: A heteroaromaticring of 5 or 6 members containing 1 or 2 heteroatoms selected from amongoxygen, nitrogen and sulphur, optionally substituted by 1 or 2 halogenatoms, by a C₁-C₄ alkyl radical or by a phenyl radical or a heteroarylradical with 5 or 6 members containing 1 or 2 atoms of oxygen, nitrogenor sulphur; A bicyclic heteroaromatic ring containing 1 to 3 heteroatomsselected from among oxygen, nitrogen and sulphur, optionally substitutedby 1 or 2 halogen atoms or by a C₁-C₄ alkyl radical; A group selectedfrom among:

R₁ represents hydrogen, a C₁-C₄ alkyl radical or a benzyl radical; nrepresents 0, 1, 2, 3 or 4; R₂ represents —NR₄R₅ or a group withformula:

wherein the dotted line represents an optional chemical bond; and R₃,R₄, and R₅ independently represent hydrogen or a C₁-C₄ alkyl; X, Y and Zindependently represent hydrogen, fluorine, chlorine, bromine, a C₁-C₄alkyl, a C₁-C₄ alkoxy, a C₁-C₄ alkylthio, trifluoromethyl, cyano, nitroand —NR₄R₅; W represents a bond between the two rings, CH₂, O, S andNR₄; m represents 0, 1, 2, 3 or 4; with the condition that when m=0, Ais a substituted phenyl; or one of its physiologically acceptable salts;said process comprising the steps of: reacting a compound with thegeneral formula (II), or one of its suitably protected derivatives,

wherein A is as indicated previously in the general formula (I), and Xis a suitable leaving group including an halogen atom, particularlychlorine; with a 5-aminoindole with the general formula (III), or one ofits suitably protected derivatives;

wherein n, R₁, R₂ and R₃ are as indicated above in the general formula(I); in order to obtain the corresponding sulphonamide, and optionallyit is possible to remove eventually the protective groups from it. 2.Process for preparing a derivative of sulphonamide with the generalformula (I), according to claim 1, wherein R₁, R₂, R₄, n and A are asindicated above in claim 1, and R₃ represents a C₁-C₄ alkyl,characterized by reacting a compound with the general formula (I),wherein R₁, R₂, R₄, n and A are as indicated above in claim 1, and R₃represents an atom of hydrogen, with an alkyl halide or dialkylsulphate.
 3. Process for preparing a derivative of sulphonamide with thegeneral formula (I), according to claim 1, wherein R₁, R₃, and A are asindicated above in claim 1, n=0 and R₂ represents a1,2,3,6-tetrahydropyridin-4-yl radical substituted in position 1 with anR₁ radical, characterized by reacting a compound with the generalformula (I), wherein R₁, R₃, and A are as indicated above in claim 1,n=0and R₂ represents an atom of hydrogen, with a 4-piperidonesubstituted in position 1 with an R₁ radical.
 4. Process for preparing aderivative of sulphonamide with the general formula (I), according toclaim 1, wherein R₁, R₃, and A are as indicated above in claim 1, n=0and R₂ represents a 4-piperidinyl radical substituted in position 1 withan R₁ radical, by reduction of a compound with the general formula (I)wherein R₁, R₃, and A are as indicated above in claim 1, n=0and R₂represents a 1,2,3,6-tetrahydropyridin-4-yl radical substituted inposition 1 with an R₁ radical.
 5. A process for preparation ofphysiologically acceptable salts of the compounds with the generalformula (I), according to claim 1, consisting in making react a compoundwith the general formula (I) with a mineral acid or an organic acid in asuitable solvent.
 6. A method for preventing or treating anxiety,depression, cognitive memory disorders and senile dementia processes andother dementias where a cognition deficit is predominant, psychosis,infantile hyperkinesia (ADHD, attention deficit/hyperactivity disorder)and other disorders mediated by the 5-HT₆ receptor of serotonin inmammals, including man, comprising administering a therapeuticallyeffective amount of a derivative of sulphonamide with the generalformula (1),

wherein A represents a substituent selected from among: A heteroaromaticring of 5 or 6 members containing 1 or 2 heteroatoms selected from amongoxygen, nitrogen and sulphur, optionally substituted by 1 or 2 halogenatoms, by a C₁-C₄ alkyl radical or by a phenyl radical or a heteroarylradical with 5 or 6 members containing 1 or 2 atoms of oxygen, nitrogenor sulphur; A bicyclic heteroaromatic ring containing 1 to 3 heteroatomsselected from among oxygen, nitrogen and sulphur, optionally substitutedby 1 or 2 halogen atoms or by a C₁-C₄ alkyl radical; A group selectedfrom among:

R₁ represents hydrogen, a C₁-C₄ alkyl radical or a benzyl radical; nrepresents 0, 1, 2, 3 or 4; R₂ represents —NR₄R₅ or a group withformula:

wherein the dotted line represents an optional chemical bond; R₃, R₄ yR₅ independently represent hydrogen or a C₁-C₄ alkyl; X, Y and Zindependently represent hydrogen, fluorine, chlorine, bromine, a C₁-C₄alkyl, a C₁-C₄ alkoxy, a C₁-C₄ alkylthio, trifluoromethyl, cyano, nitroand —NR₄R₅; W represents a bond between the two rings, CH₂, O, S andNR₄; m represents 0, 1, 2, 3 or 4; or one of its physiologicallyacceptable salts, to a mammal in need thereof.